CoChat
Sign Up
Cited by 51Folate and B Vitamins ResearchGlobal Cancer Incidence and ScreeningAcute Lymphoblastic Leukemia research

Childhood Cancer Incidence Trends in Association With US Folic Acid Fortification (1986–2008)

Open access
Linabery, Amy M., Johnson, Kimberly J., Ross, Julie A.·2012·Pediatrics
DOI 10.1542/peds.2011-3418PMC PMC3362910
Open this paper in CoChat — free accountOpen PDF

Abstract

OBJECTIVE: Epidemiologic evidence indicates that prenatal vitamin supplementation reduces risk for some childhood cancers; however, a systematic evaluation of population-based childhood cancer incidence trends after fortification of enriched grain products with folic acid in the United States in 1996–1998 has not been previously reported. Here we describe temporal trends in childhood cancer incidence in association with US folic acid fortification. METHODS: Using Surveillance, Epidemiology, and End Results program data (1986–2008), we calculated incidence rate ratios and 95% confidence intervals to compare pre- and postfortification cancer incidence rates in children aged 0 to 4 years. Incidence trends were also evaluated by using joinpoint and loess regression models. RESULTS: From 1986 through 2008, 8829 children aged 0 to 4 years were diagnosed with malignancies, including 3790 and 3299 in utero during the pre- and postfortification periods, respectively. Pre- and postfortification incidence rates were similar for all cancers combined and for most specific cancer types. Rates of Wilms tumor (WT), primitive neuroectodermal tumors (PNETs), and ependymomas were significantly lower postfortification. Joinpoint regression models detected increasing WT incidence from 1986 through 1997 followed by a sizable decline from 1997 through 2008, and increasing PNET incidence from 1986 through 1993 followed by a sharp decrease from 1993 through 2008. Loess curves indicated similar patterns. CONCLUSIONS: These results provide support for a decrease in WT and possibly PNET incidence, but not other childhood cancers, after US folic acid fortification.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1542/peds.2011-3418

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Ancestry is known to alter both pediatric ALL incidence and survival.

    “Similarly, ancestry, which is known to alter both pediatric ALL incidence and survival (Abrahão et al., 2015; Goggins & Lo, 2012; Linabery, Johnson, & Ross, 2012), is likely to also impact the risk and severity of late effects (Bhatia et al., 2002; Dores, Devesa, Curtis, Linet, & Morton, 2012; Lim, Bhatia, Robison, & Yang, 2014; Yang et al., 2010).”

    From Brain structure, working memory and response inhibition in childhood leukemia survivors (2017) · cites this paper as Linabery et al., 2012

    The Methods and Results report pediatric lymphoid leukemia incidence in relation to folic acid fortification, not ancestry. A passage under Figure 1 compares racial and ethnic distributions in SEER and the US population but does not link ancestry to ALL incidence or survival. Searches for ancestry, race, ethnicity, and survival found no passage addressing the attributed claim; pages were not provided in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 67 · Cited by 51

Research works printed but not linked: 57

  1. MRC Vitamin Study Research Group. Pre- vention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338(8760):131-137
  2. Czeizel AE, Dobo M, Vargha P. Hungarian cohort-controlled trial of periconceptional multivitamin supplementation shows a re- duction in certain congenital abnormalities. Birth Defects Res. 2004;70(11):853-861
  3. Food and Drug Administration. Food stan- dards: amendment of standards of identity for enriched grain products to require ad- dition of folic acid. Fed Regist. 1996;61:8781- 8797
  4. Yeung L, Yang Q, Berry RJ. Contributions of total daily intake of folic acid to serum folate concentrations. JAMA. 2008;300(21): 2486-2487
  5. Centers for Disease Control. Folate status in women of childbearing age-United States, 1999. MMWR Morb Mortal Wkly Rep. 2000;49 (42):962-965
  6. Williams LJ, Mai CT, Edmonds LD, et al. Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States. Ter- atology. 2002;66(1):33-39
  7. Grupp SG, Greenberg ML, Ray JG, et al. Pediatric cancer rates after universal folic acid flour fortification in Ontario. J Clin Pharmacol. 2011;51(1):60-65
  8. French AE, Grant R, Weitzman S, et al. Folic acid food fortification is associated with a decline in neuroblastoma. Clin Pharma- col Ther. 2003;74(3):288-294
  9. Bunin GR, Meadows AT, Emanuel BS, Buckley JD, Woods WG, Hammond GD. Pre-and postconception factors associated with spo- radic heritable and nonheritable retinoblas- toma. Cancer Res. 1989;49(20):5730-5735
  10. Bunin GR, Kuijten RR, Buckley JD, Rorke LB, Meadows AT. Relation between maternal diet and subsequent primitive neuroecto- dermal brain tumors in young children. N Engl J Med. 1993;329(8):536-541
  11. Bunin GR, Kuijten RR, Boesel CP, Buckley JD, Meadows AT. Maternal diet and risk of astrocytic glioma in children: a report from the Childrens Cancer Group (United States and Canada). Cancer Causes Control. 1994; 5(2):177-187
  12. Sarasua S, Savitz DA. Cured and broiled meat consumption in relation to childhood cancer: Denver, Colorado (United States). Cancer Causes Control. 1994;5(2):141-148
  13. Michalek AM, Buck GM, Nasca PC, Freedman AN, Baptiste MS, Mahoney MC. Gravid health status, medication use, and risk of neuro- blastoma. Am J Epidemiol. 1996;143(10): 996-1001
  14. Preston-Martin S, Pogoda JM, Mueller BA, Holly EA, Lijinsky W, Davis RL. Maternal consumption of cured meats and vitamins in relation to pediatric brain tumors. Can- cer Epidemiol Biomarkers Prev. 1996;5(8): 599-605
  15. Preston-Martin S, Pogoda JM, Mueller BA, et al. Prenatal vitamin supplementation and risk of childhood brain tumors. Int J Cancer Suppl. 1998;11:17-22
  16. Thompson JR, Gerald PF, Willoughby ML, Armstrong BK. Maternal folate supplemen- tation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: a case-control study. Lancet. 2001;358(9297): 1935-1940
  17. Wen W, Shu XO, Potter JD, et al. Parental medication use and risk of childhood acute lymphoblastic leukemia. Cancer. 2002;95(8): 1786-1794
  18. Olshan AF, Smith JC, Bondy ML, Neglia JP, Pollock BH. Maternal vitamin use and re- duced risk of neuroblastoma. Epidemiol- ogy. 2002;13(5):575-580
  19. Bunin GR, Gallagher PR, Rorke-Adams LB, Robison LL, Cnaan A. Maternal supplement, micronutrient, and cured meat intake during pregnancy and risk of medullo- blastoma during childhood: a Children' s Oncology Group study. Cancer Epidemiol Biomarkers Prev. 2006;15(9):1660-1667
  20. Schüz J, Weihkopf T, Kaatsch P. Medication use during pregnancy and the risk of childhood cancer in the offspring. Eur J Pediatr. 2007;166(5):433-441
  21. Gale KB, Ford AM, Repp R, et al. Back- tracking leukemia to birth: identification of clonotypic gene fusion sequences in neo- natal blood spots. Proc Natl Acad Sci USA. 1997;94(25):13950-13954
  22. Taub JW, Ge Y. The prenatal origin of childhood acute lymphoblastic leukemia. Leuk Lymphoma. 2004;45(1):19-25
  23. Greaves MF, Maia AT, Wiemels JL, Ford AM. Leukemia in twins: lessons in natural his- tory. Blood. 2003;102(7):2321-2333
  24. Woodward PJ, Sohaey R, Kennedy A, Koeller KK. From the archives of the AFIP: a com- prehensive review of fetal tumors with pathologic correlation. Radiographics. 2005; 25(1):215-242
  25. Pizzo PA, Poplack DG. Principles and Practice of Pediatric Oncology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006
  26. Zippin C, Lum D, Hankey BF. Completeness of hospital cancer case reporting from the SEER Program of the National Cancer In- stitute. Cancer. 1995;76(11):2343-2350
  27. Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. International Classification of Childhood Cancer, third edition. Cancer. 2005;103(7):1457-1467
  28. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med. 2000;19(3):335-351
  29. Cohen RA. An Introduction to PROC LOESS for local regression. Proceedings of the 24th SAS Users Group International Con- ference, Miami, FL, April 1999; Paper 273.
  30. Blount BC, Mack MM, Wehr CM, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome break- age: implications for cancer and neuronal damage. Proc Natl Acad Sci USA. 1997;94 (7):3290-3295
  31. Kim YI. Folic acid supplementation and cancer risk: point. Cancer Epidemiol Bio- markers Prev. 2008;17(9):2220-2225
  32. Centers for Disease Control and Prevention (CDC). Use of supplements containing folic acid among women of childbearing age- United States, 2007. MMWR Morb Mortal Wkly Rep. 2008;57(1):5-8
  33. Caughey RW, Michels KB. Birth weight and childhood leukemia: a meta-analysis and review of the current evidence. Int J Can- cer. 2009;124(11):2658-2670
  34. Harder T, Plagemann A, Harder A. Birth weight and subsequent risk of childhood primary brain tumors: a meta-analysis. Am J Epidemiol. 2008;168(4):366-373
  35. Schüz J, Schmidt LS, Kogner P, et al. Birth characteristics and Wilms tumors in chil- dren in the Nordic countries: a register- based case-control study. Int J Cancer. 2011;128(9):2166-2173
  36. Puumala SE, Soler JT, Johnson KJ, Spector LG. Birth characteristics and Wilms tumor in Minnesota. Int J Cancer. 2008;122(6): 1368-1373
  37. Ognjanovic S, Carozza SE, Chow EJ, et al. Birth characteristics and the risk of child- hood rhabdomyosarcoma based on histo- logical subtype. Br J Cancer. 2010;102(1): 227-231
  38. Ly A, Lee H, Chen J, et al. Effect of maternal and postweaning folic acid supplementa- tion on mammary tumor risk in the off- spring. Cancer Res. 2011;71(3):988-997
  39. Sie KK, Medline A, van Weel J, et al. Effect of maternal and postweaning folic acid supplementation on colorectal cancer risk in the offspring. Gut. 2011;60(12):1687-1694
  40. Spector LG, Johnson KJ, Soler JT, Puumala SE. Perinatal risk factors for hepatoblastoma. Br J Cancer. 2008;98(9):1570-1573
  41. Birch JM, Marsden HB. A classification scheme for childhood cancer. Int J Cancer. 1987;40(5):620-624
  42. Kramárová E, Stiller CA. The international classification of childhood cancer. Int J Cancer. 1996;68(6):759-765
  43. Scheithauer BW. Development of the WHO classification of tumors of the central ner- vous system: a historical perspective. Brain Pathol. 2009;19(4):551-564
  44. Delemarre JF, Sandstedt B, Harms D, Boccon- Gibod L, Vujani c GM; International Society of Paediatric Oncology. The new SIOP (Stock- holm) working classification of renal tumours of childhood. Med Pediatr Oncol. 1996;26(2): 145-146
  45. Wright AJ, Dainty JR, Finglas PM. Folic acid metabolism in human subjects revisited: potential implications for proposed man- datory folic acid fortification in the UK. Br J Nutr. 2007;98(4):667-675
  46. Preston-Martin S, Yu MC, Benton B, Henderson BE. N-Nitroso compounds and childhood brain tumors: a case-control study. Cancer Res. 1982;42(12):5240-5245
  47. Lubin F, Farbstein H, Chetrit A, et al. The role of nutritional habits during gestation and child life in pediatric brain tumor eti- ology. Int J Cancer. 2000;86(1):139-143
  48. Dockerty JD, Herbison P, Skegg DC, Elwood M. Vitamin and mineral supplements in pregnancy and the risk of childhood acute lymphoblastic leukaemia: a case-control study. BMC Public Health. 2007;7:136
  49. Milne E, Royle JA, Miller M, et al. Maternal folate and other vitamin supplementation during pregnancy and risk of acute lym- phoblastic leukemia in the offspring. Int J Cancer. 2010;126(11):2690-2699
  50. Robison LL, Buckley JD, Daigle AE, et al. Maternal drug use and risk of childhood nonlymphoblastic leukemia among offspring. An epidemiologic investigation implicat- ing marijuana (a report from the Childrens Cancer Study Group). Cancer. 1989;63(10): 1904-1911
  51. Pombo-de-Oliveira MS, Koifman S; Brazilian Collaborative Study Group of Infant Acute Leukemia. Infant acute leukemia and ma- ternal exposures during pregnancy. Cancer Epidemiol Biomarkers Prev. 2006;15(12): 2336-2341
  52. Buckley JD, Sather H, Ruccione K, et al. A case-control study of risk factors for hepatoblastoma. A report from the Child- rens Cancer Study Group. Cancer. 1989;64(5): 1169-1176
  53. Shu XO, Nesbit ME, Buckley JD, Krailo MD, Robinson LL. An exploratory analysis of risk factors for childhood malignant germ-cell tumors: report from the Childrens Cancer Group (Canada, United States). Cancer Causes Control. 1995;6(3):187-198
  54. Johnson KJ, Poynter JN, Ross JA, Robison LL, Shu XO. Pediatric germ cell tumors and maternal vitamin supplementation: a Child- ren' s Oncology Group study. Cancer Epidemiol Biomarkers Prev. 2009;18(10):2661-2664
  55. Duthie SJ. Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull. 1999;55(3):578-592
  56. Kim YI. Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Bio- chem. 1999;10(2):66-88
  57. Wilson AS, Power BE, Molloy PL. DNA hypo- methylation and human diseases. Biochim Biophys Acta. 2007;1775(1):138-162

Authors
Linabery, A. M., Johnson, K. J., & Ross, J. A.
Affiliations
  • University of Minnesota (US)
  • Washington University in St. Louis (US)
Corresponding author
Linabery, Amy M.
ORCID
Venue
Pediatrics
Publisher
American Academy of Pediatrics (AAP)
Published
2012-06-01
Volume
129
Issue
6
Pages
1125-1133
ISSN
  • 0031-4005 (ISSN-L)
  • 1098-4275
DOI
10.1542/peds.2011-3418
PMC
PMC3362910
OpenAlex
W2132331467
Cited by
51
References
67
Citations by year
2026: 1 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 5 · 2021: 3 · 2020: 5 · 2018: 2 · 2017: 1 · 2016: 4 · 2015: 8 · 2014: 6 · 2013: 4 · 2012: 1
FWCI
4.67
Type
journal article
Language
en
Open access
Locations
  • PEDIATRICS (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (K05CA157439, T32CA099936)
Topics
  • Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
  • Health Sciences › Medicine › Oncology › Global Cancer Incidence and Screening
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
Keywords
folic acid fortification, childhood cancer incidence, grain fortification, prenatal vitamin supplementation, Wilms tumor, primitive neuroectodermal tumor, ependymoma, incidence trends, cancer prevention
MeSH terms
Child, Preschool, Female, Folic Acid, Food, Fortified, Humans, Infant, Infant, Newborn, Male, Neoplasms, Nutrition Surveys, Registries, United States, Incidence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review